Intensive studies in the past decade have shown that cardiac myocyte death, which has characteristics of apoptosis, occurs in response to ischemia/reperfusion (I/R) and during cardiac remodeling after myocardial infarction (1–9). Although controversies still exist regarding the occurrence of apoptosis vs oncosis in the ischemic heart (10,11), it seems established that the signaling mechanisms promoting myocyte cell death, including caspases, are activated by I/R and in cardiomyopathy (12–16) (reviewed in 47). Recent evidence suggests that myocyte proliferation could take place in response to the loss of cardiac myocyte after myocardial infarction (17). However, considering the limited capacity of terminally differentiated cardiac myocytes for proliferation, it is important to understand how these cell death promoting signaling mechanisms are activated by I/R and in myopathic hearts in order to establish interventions efficiently preventing the cell loss in various stages of heart diseases (10). It has been shown that intracellular stress-responsive protein kinases, including JNKs and p38-MAPKs, are activated by I/R in the heart (18–23). Although these kinases are likely to affect both cell death and cell survival, the roles of the stress-responsive protein kinases (SRPKs) in cardiac myocyte apoptosis are not fully understood. Furthermore, the SRPK selectively promoting cardiac myocyte apoptosis has not been identified in vivo.
Mst1 (mammalian sterile 20-like kinase-1) is a ubiquitously expressed serine/threonine kinase (24,25), which belongs to a mammalian sterile 20 (STE 20)-like kinase family consisting of Pak1, Mst 1, Mst2, Khs, Gck, Sok1, Nik, Hpk1 and Sps1 (26,27). Increasing lines of evidence suggest that Mst1 and other STE20-like family kinases play an important role in mediating apoptosis (reviewed in (27)). Mst 1 is activated by some pro-apoptotic stimuli in fibroblastic and lymphocytic cell lines. However, stimuli shown to activate Mst1 are generally limited to non-physiological stresses, including genotoxic compounds and extreme heat shock (25,28–31). Mst1 can be an efficient mediator of apoptosis because it is cleaved by caspases and this cleavage increases kinase activities of Mst1, which in turn activates caspase 3 (32), thereby constituting a powerful amplification loop of apoptotic response (33). Importantly, however, whether or not activation of Mst1 is required for in vivo cell death in response to clinically relevant pathologic insults has not been determined in any organs, including the heart.
Despite a growing understanding that apoptosis plays a physiological role and potentially pathological role in the heart there still exists a significant need in the art for methods and agents for treatment, amelioration and prevention of cardiac disease, including cardiac myopathy, chronic heart failure and for management and reduction of cardiac myocyte death which may occur in response to ischemia/reperfusion or following myocardial infarction or other injury to the heart.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.